论文部分内容阅读
目的获得抗炎活性强、胃肠道不良反应小的新型非甾体抗炎药 (NSAIDs)。方法将具有不同释放机制的一氧化氮 (NO)供体 ,包括NO合酶 (NOS)底物类似物、硝酸酯和呋咱氮氧化物通过酯键与正在Ⅲ期临床研究的NSAID氟罗布芬 (1 )相偶联 ,测定偶联物的抗炎活性 ,考察其胃肠道毒副作用 ,研究其释放NO的作用。结果合成 1 9个未见文献报道的新化合物 ,结构经MS、IR、1H NMR和元素分析确证。初步药理筛选结果表明 :1 0个目标物 (Ⅰ1、Ⅰ3～ 5、Ⅰ8、Ⅰ12 、Ⅱ2 ,3 、Ⅱ6,7)显示了较高的抗炎活性 ,其中 5个 (Ⅰ1、Ⅰ3 ,4、Ⅱ3 、Ⅱ6)活性与氟罗布芬相当 (P >0 0 5 ) ;所有活性化合物均表现出较小的胃肠道不良反应 ,其中Ⅰ1、Ⅰ3 、Ⅰ5、Ⅱ7的不良反应显著小于氟罗布芬 (P <0 0 5 )。结论Ⅰ1和Ⅰ3 的综合指标优于氟罗布芬 ,值得深入研究。
Objective To obtain new non-steroidal anti-inflammatory drugs (NSAIDs) with strong anti-inflammatory activity and small gastrointestinal adverse reactions. Methods Nitric oxide (NO) donors with different release mechanisms, including NO synthase (NOS) substrate analogs, nitrates and furazan oxynitrides, were coupled via ester bonds to the NSAIDs Flunbufen (1), the anti-inflammatory activity of the conjugate was tested, the gastrointestinal side effects were investigated, and the release of NO was studied. Results Nineteen new compounds were synthesized and their structures were confirmed by MS, IR, 1H NMR and elemental analysis. Preliminary pharmacological screening results showed that 10 of the 10 targets (I1, I3-5, I8, I12, II2, 3, II6,7) showed higher antiinflammatory activity, of which 5 (I1, I3, 4, (P> 0.05). All the active compounds showed small gastrointestinal adverse reactions, of which the adverse reactions of Ⅰ 1, Ⅰ 3, Ⅰ 5 and Ⅱ 7 were significantly less than those of vasopressin <0 0 5). Conclusion The comprehensive indexes of Ⅰ 1 and Ⅰ 3 are better than that of flunbufen, which deserves further study.